The complement factor H R1210C mutation is associated with atypical hemolytic uremic syndrome

Abstract

Mutations in the gene encoding complement factor H (CFH) that alter the C3b/polyanions-binding site in the C-terminal region impair the capacity of factor H to protect host cells. These mutations are also strongly associated with atypical hemolytic uremic syndrome (aHUS). Although most of the aHUS-associated CFH mutations seem “unique” to an individual patient or family, the R1210C mutation has been reported in several unrelated aHUS patients from distinct geographic origins. Five aHUS pedigrees and 7 individual aHUS patients were analyzed to identify potential correlations between the R1210C mutation and clinical phenotype and to characterize the origins of this mutation. The clinical phenotype of aHUS patients carrying the R1210C mutation was heterogeneous. Interestingly, 12 of the 13 affected patients carried at least one additional known genetic risk factor for aHUS. These data are in accord with the 30% penetrance of aHUS in R1210C mutation carriers, as it seems that the presence of other genetic or environmental risk factors significantly contribute to the manifestation and severity of aHUS in these subjects. Genotype analysis of CFH and CFHR3 polymorphisms in the 12 unrelated carriers suggested that the R1210C mutation has a single origin. In conclusion, the R1210C mutation of complement factor H is a prototypical aHUS mutation that is present as a rare polymorphism in geographically separated human populations.

HUS is characterized by thrombocytopenia, Coomb's test negative microangiopathic hemolytic anemia, and acute renal failure. The typical form of HUS follows a diarrheal prodrome and is associated with Shiga toxin-producing 0157:H7 Escherichia coli infections. However, 5% to 10% of HUS patients lack an association with infection. This atypical form of HUS (aHUS) occurs in both adults and in young children and has a poor prognosis. Recurrent episodes of aHUS are common with a mortality rate that approaches 30%. Endothelial cell injury appears to be the primary event in the pathogenesis of HUS. The endothelial damage triggers a cascade of events that result in the formation of platelet-fibrin hyaline microthrombi that occlude arterioles and capillaries. A hallmark of HUS is the presence of schistocytes (fragmented cells) that generate as the red blood cells traverse these partially occluded microvessels.

aHUS is associated with mutations or polymorphisms in the genes encoding the complement regulatory proteins factor H (CFH),2–9 membrane cofactor protein (MCP, CD46),10–13 and factor I (IF, CFI),14,15 and with mutations in the complement activating components factor B (BF, CFB)16 and C3 (C3).17 Importantly, mutations in CFH, MCP (CD46), and IF (CFI) are loss-of-function mutations, whereas mutations in BF (CFB) are gain-of-function mutations. In addition, autoantibodies and deletion of the CFHR1-CFHR3 genes are associated with aHUS.18–20

Missense mutations in the exons encoding the C-terminal region of factor H are the commonest genetic alteration among aHUS patients. Carriers of these CFH mutations express factor H molecules that present normal regulatory activity in plasma but a limited capacity to protect cells from complement lysis.4,7,21 The combination of both an active complement system in plasma and a defective protection of cellular surfaces is critical in the pathogenesis of aHUS.22 In a situation that triggers complement activation, such as during bacterial or viral infections, exposure to drugs that cause endothelial activation and damage or the presence of immune complexes, deposition, and amplification of C3b on the microvasculature cellular surfaces cannot be controlled, and this results in tissue damage and destruction.

CFHR1210C is the prototypic aHUS-associated CFH mutation. Functional analysis demonstrated that R1210C mutant factor H has normal cofactor activity but defective binding to C3b, heparin, and endothelial cells.4,7 A unique feature of the R1210C factor H mutant is its capacity to form covalent heterodimers with serum albumin through the cysteine residue generated by the mutation.7 Interestingly, CFHR1210C is a common mutation that has been described in several unrelated aHUS patients from different countries.2,3,7,23,24

Here we have both examined whether there is a common clinical phenotype associated with CFHR1210C and analyzed the origins of this mutation. To this end, we evaluated in 13 aHUS patients and 16 healthy carriers the clinical phenotypes, determined the CFH genotypes associated with CFHR1210C, and analyzed the concurrence of other known aHUS risk factors. These include mutations and polymorphisms in the CFH, MCP (CD46), and IF (CFI) genes, and genomic rearrangements in the CFH-CFHR1–5 genomic region